We propose that protective CNS immunity can be generated by the interactions between brain mononuclear phagocytes (MP; macrophages and microglia) and CD8+ T lymphocytes. These occur in distinct manner, either through elimination of infected cells (the generation of cytotoxic T lymphocytes, CTL) or by T cell mediated neuroprotection. The proposal seeks to study how the brain is protected against a relentless attack by virus for many years and in most infected people. Furthermore, we suggest that the production of potent neurotrophic factors and the destruction of virus-related cells in the central nervous system (CNS) occurs as a consequences of MP activation. Based on these observations, we propose that the pathways of CNS immune activation regulate the destructive or trophic potential of the brain macrophages or microglia. To investigate mechanisms for immune-based neuroprotection during HIV infection, we will test T cell and nerve injury-mediated MP activation for the regulation of effector cell function in laboratory and animal model HIV CNS disease systems. For the latter, HIV-1 infected brain macrophages injected into the subcortex of immunodeficient mice induce potent HIV-1 specific CTL and neuroprotective activities resulting in the rapid elimination of infected cells and neuronal sparing. The role of specific HIV-1 strain in this response and the coordinate effects on inflammatory responses of the brain will be studied. The overall goal of these works is to determine the relative role of innate and acquired immunity to both control ongoing viral production and affect ways to protect neurons against injuries initiated by virus-infected MP. The central question being addressed are on defining the role of the peripheral immune system in protecting the brain against HIV-1 medicated injury for most of sub-clinical disease. This is a most important yet understudied question in HIV-1 neuropathogenesis with applicability to a whole range of neurodegenerative disorders. This project serves as an extension of our previous works seeking to determine how microglial immunity affects the pathogenesis, progression and the therapeutic options for HAD. [unreadable] [unreadable]